A methodology to establish a database to study gene environment interactions for childhood asthma

BackgroundGene-environment interactions are likely to explain some of the heterogeneity in childhood asthma. Here, we describe the methodology and experiences in establishing a database for childhood asthma designed to study gene-environment interactions (PAGES - Paediatric Asthma Gene Environment Study).MethodsChildren with asthma and under the care of a respiratory paediatrician are being recruited from 15 hospitals between 2008 and 2011. An asthma questionnaire is completed and returned by post. At a routine clinic visit saliva is collected for DNA extraction. Detailed phenotyping in a proportion of children includes spirometry, bronchodilator response (BDR), skin prick reactivity, exhaled nitric oxide and salivary cotinine. Dietary and quality of life questionnaires are completed. Data are entered onto a purpose-built database.ResultsTo date 1045 children have been invited to participate and data collected in 501 (48%). The mean age (SD) of participants is 8.6 (3.9) years, 57% male. DNA has been collected in 436 children. Spirometry has been obtained in 172 children, mean % predicted (SD) FEV1 97% (15) and median (IQR) BDR is 5% (2, 9). There were differences in age, socioeconomic status, severity and %FEV1 between the different centres (p≤0.024). Reasons for non-participation included parents not having time to take part, children not attending clinics and, in a small proportion, refusal to take part.ConclusionsIt is feasible to establish a national database to study gene-environment interactions within an asthmatic paediatric population; there are barriers to participation and some different characteristics in individuals recruited from different centres. Recruitment to our study continues and is anticipated to extend current understanding of asthma heterogeneity.

[1]  M. Beauchesne,et al.  Development and validation of database indexes of asthma severity and control , 2007, Thorax.

[2]  E. Sims,et al.  Potential benefits of the UK Cystic Fibrosis Database. , 2004, Journal of the Royal Society of Medicine.

[3]  Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide in Adults and Children — 1999 , 1999 .

[4]  Anil Mehta,et al.  Comparative analysis of Cystic Fibrosis Registry data from the UK with USA, France and Australasia. , 2005, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[5]  A. Woodcock,et al.  Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment. , 2006, American journal of respiratory and critical care medicine.

[6]  L. Palmer,et al.  β2 adrenoceptor Arg16Gly polymorphism, airway responsiveness, lung function and asthma in infants and children , 2004 .

[7]  J. Gustafson,et al.  Cystic Fibrosis , 2009, Journal of the Iowa Medical Society.

[8]  S. Gabriel,et al.  Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. , 2004, Human molecular genetics.

[9]  G. Morahan,et al.  Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children , 2002, The Lancet.

[10]  C. Feyerabend,et al.  What determines levels of passive smoking in children with asthma? , 1997, Thorax.

[11]  N. Heinrichs,et al.  Parent Recruitment and Retention in a Universal Prevention Program for Child Behavior and Emotional Problems: Barriers to Research and Program Participation , 2005, Prevention Science.

[12]  G. Russell,et al.  Respiratory symptoms and atopy in children in Aberdeen: questionnaire studies of a defined school population repeated over 35 years , 2004, BMJ : British Medical Journal.

[13]  E. Mutius.  Gene-environment interactions in asthma , 2009 .

[14]  J. Spinelli,et al.  Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. , 2000, The Journal of allergy and clinical immunology.

[15]  S. Ogston,et al.  Asians with cystic fibrosis in the UK have worse disease outcomes than clinic matched white homozygous delta F508 controls. , 2005, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[16]  D. Mannino,et al.  Involuntary smoking and asthma severity in children: data from the Third National Health and Nutrition Examination Survey. , 2002, Chest.

[17]  J. Ayres,et al.  Household chemicals, persistent wheezing and lung function: effect modification by atopy? , 2008, European Respiratory Journal.

[18]  J. McCormick,et al.  Demographics of the UK cystic fibrosis population: implications for neonatal screening , 2002, European Journal of Human Genetics.

[19]  Fernando Holguin,et al.  Asthma Phenotypes, Risk Factors, and Measures of Severity in a National Sample of US Children , 2005, Pediatrics.

[20]  N Franklin Adkinson,et al.  Long-term effects of budesonide or nedocromil in children with asthma. , 2000, The New England journal of medicine.

[21]  I. Romieu,et al.  Antioxidant supplementation and lung functions among children with asthma exposed to high levels of air pollutants. , 2002, American journal of respiratory and critical care medicine.

[22]  W D Flanders,et al.  Sample size requirements in case-only designs to detect gene-environment interaction. , 1997, American journal of epidemiology.

[23]  L. Leng,et al.  Role for macrophage migration inhibitory factor in asthma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[24]  T H Beaty,et al.  Minimum sample size estimation to detect gene-environment interaction in case-control designs. , 1994, American journal of epidemiology.

[25]  B. Lipworth,et al.  Arginine-16 β2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol , 2006, Thorax.

[26]  Colin N A Palmer,et al.  Filaggrin null mutations are associated with increased asthma severity in children and young adults. , 2007, The Journal of allergy and clinical immunology.

[27]  G. Heldt,et al.  Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. , 2005, The Journal of allergy and clinical immunology.

[28]  J. Tonascia,et al.  Budesonide and nedocromil did not improve lung function in children with asthma The Childhood Asthma Management Program Research Group. Long›term effects of budesonide or nedocromil in children , 2001 .

[29]  S. Stanojevic,et al.  Reference ranges for spirometry across all ages: a new approach. , 2008, American journal of respiratory and critical care medicine.

[30]  E. Sims,et al.  Decreased lung function in female but not male subjects with established cystic fibrosis-related diabetes. , 2005, Diabetes care.

[31]  S. Weiss,et al.  Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between beta-agonist and corticosteroid pathways. , 2005, Human molecular genetics.

[32]  S. Turner,et al.  Validation of a hand‐held exhaled nitric oxide analyzer for use in children , 2006, Pediatric pulmonology.

[33]  P. Helms,et al.  Spirometry in 5‐year‐olds—validation of current guidelines and the relation with asthma , 2007, Pediatric pulmonology.

[34]  S. Weiss,et al.  TBX21: A functional variant predicts improvement in asthma with the use of inhaled corticosteroids , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[35]  P. Phelan,et al.  The Melbourne Asthma Study: 1964-1999. , 2002, The Journal of allergy and clinical immunology.

[36]  D. Postma,et al.  Childhood factors associated with asthma remission after 30 year follow up , 2004, Thorax.

[37]  C. Palmer,et al.  A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. , 2008, The Journal of allergy and clinical immunology.

[38]  L. Palmer,et al.  The relationship between infant airway function, childhood airway responsiveness, and asthma. , 2004, American journal of respiratory and critical care medicine.

[39]  J. Hankinson,et al.  Standardisation of spirometry , 2005, European Respiratory Journal.

[40]  E. Robles,et al.  Relationship of body mass index with asthma indicators in head start children. , 2007, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[41]  F COLYER.  Asymmetry of the Dental Arch in a Toque Monkey (MacAca Sinica) , 1951, Proceedings of the Royal Society of Medicine.

[42]  E. Silverman,et al.  CD14 tobacco gene-environment interaction modifies asthma severity and immunoglobulin E levels in Latinos with asthma. , 2005, American journal of respiratory and critical care medicine.

[43]  M J Khoury,et al.  Commentary: facing the challenge of gene-environment interaction: the two-by-four table and beyond. , 2001, American journal of epidemiology.

[44]  J. Pepys.  Skin tests for immediate, type I, allergic reactions. , 1972, Proceedings of the Royal Society of Medicine.

[45]  S. London,et al.  Parental Smoking Modifies the Relation between Genetic Variation in Tumor Necrosis Factor-α (TNF) and Childhood Asthma , 2007, Environmental health perspectives.